Crossing paths in Human Renal Cell Carcinoma (hRCC).

Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.

State of the art in silico tools for the study of signaling pathways in cancer.

In the last several years, researchers have exhibited an intense interest in the evolutionarily conserved signaling pathways that have crucial roles during embryonic development. Interestingly, the malfunctioning of these signaling pathways leads to several human diseases, including cancer. The chemical and biophysical events that occur during cellular signaling, as well as the number of interactions within a signaling pathway, make these systems complex to study. In silico resources are tools used to aid the understanding of cellular signaling pathways. Systems approaches have provided a deeper knowledge of diverse biochemical processes, including individual metabolic pathways, signaling networks and genome-scale metabolic networks. In the future, these tools will be enormously valuable, if they continue to be developed in parallel with growing biological knowledge. In this study, an overview of the bioinformatics resources that are currently available for the analysis of biological networks is provided.

Evaluation of COX-2, EGFR, and p53 as biomarkers of non-dysplastic oral leukoplakias.

OBJECTIVE: Identify candidate SEBs (surrogate endpoint biomarkers) for premalignant trends in head and neck mucosa. STUDY DESIGN: Study, by qPCR (quantitative real-time polymerase chain reaction), the expression of COX-2, EGFR and p53 in 24 biopsies of non-dysplastic oral leukoplakia and contra-lateral normal-appearing mucosa. RESULTS: COX-2 was up-regulated in leukoplakia (79.2%); whereas EGFR and p53 were up-regulated (p>0.05) in oral contra-lateral normal-appearing mucosa (60% and 46% respectively). Also, p53 expression was correlated with tobacco smoke habits and Spearman's rank correlation coefficient showed a positive linear correlation between p53 and EGFR mRNA expression levels. CONCLUSIONS: COX-2 would serve as SEB of oral leukoplakia. The results suggest that p53 appears to be one of the molecular targets of tobacco-related carcinogens in leukoplakia and that the co-expression of p53 and EGFR may play a role in this kind of oral pre-cancerous lesion. More detailed studies of EGFR and p53 should be continued in the future.

Glucose transporter expression and the potential role of fructose in renal cell carcinoma: A correlation with pathological parameters.

All mammalian cells contain one or more members of the facilitative glucose transporter (GLUT) gene family. Glucose transporter membrane proteins (GLUT) regulate the movement of glucose between the extracellular and intracellular compartments, maintaining a constant supply of glucose available for metabolism. Tumor cells are highly energy-dependent, therefore GLUT overexpression is often observed. In fact, overexpression of GLUT1 has been correlated with hypoxia markers in several tumor types, including renal cell carcinoma (RCC). We retrospectively analyzed 80 paraffin-embedded RCC samples. The pattern of GLUT1-5 expression in RCC specimens was evaluated using tissue-array technology and correlated with histological tumor characteristics. Pathological parameters included tumor location, renal pelvis, vein and lymph vessel invasion, capsule breakage, histological subtype, Furhman grade, hilar invasion and tumor stage at diagnosis. The expression of five facilitative glucose transporters, GLUT1 (erythrocyte type), GLUT2 (liver type), GLUT3 (brain type), GLUT4 (muscle/fat type) and GLUT5 (small intestinal type), was semi-quantitatively analyzed. In non-parametric, Mann-Whitney U and Kruskal-Wallis tests, a significant positive correlation was consistently found between moderately differentiated RCC tissues and the expression of GLUT5 (p=0.024). Patients who had pelvic invasion and capsule breakage at diagnosis also showed increased GLUT5 expression levels (p=0.039 and p=0.019, respectively). Moreover, GLUT5 showed statistical significance in those samples identified as being of clear cell histological type (p=0.001). A high expression of GLUT5 in human RCC was observed. GLUT5 appears to be correlated with grade II differentiation, locoregional invasion and aggressiveness, and may play a role in RCC development.